PL207175B1 - Integrin inhibitors for the treatment of eye diseases - Google Patents

Abstract

Methods and compositions for prophylaxis and/or treatment of diseases of the eye using antagonists of the integin receptors alpha v beta 3 and/or alpha v beta 5. The compositions can be nanoparticles and are administered to the eye by injection into the vitreous body of the eye.

Description

Description of the invention

The invention relates generally to medicine, and more particularly to compositions for the prevention and / or treatment of ophthalmic diseases using antagonists of the α _ν β ₃ and / or α _ν β ₅ integrin receptors. In particular, the invention relates to the use of the α _v e ₃ and / or a _v e ₅ integrin receptor antagonists for the preparation of compositions for the prevention and / or treatment of ocular diseases, wherein the compositions are administered by intravitreal injection.

Integrins are a class of cell receptors known to bind extracellular matrix proteins, and thus mediate cell-cell and cell-extracellular matrix interactions, generally involving the phenomenon of adhesion. Integrin receptors form a family of membrane proteins sharing the structural characteristics of heterodimeric glycoprotein complexes made of α and β subunits.

One class of integrin receptors, the vitronectin receptor, named for its characteristic favorable binding to vitronectin, relates to three different integrins, described as: a _v e ₁ , a _v e ₃ and a _v e ₅ by Horton, Int. J. Exp. Pathol., 71: 741-759 (1990). a _v e ₁ binds fibronectin and vitronectin. a _v e ₃ binds many different ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand factor, osteospondin and bone sialoprotein I. a _v e ₅ binds vitronectin. The specific role of cell adhesion these three integrins play in many cellular interactions in tissues is still under investigation, but it is known that there are different integrins with different biological functions.

An important area of recognition in the ligand art for many integrins is the arginine-glycine-aspartic acid tripeptide (RGD) sequence. RGD is found in all ligands identified above for the vitronectin receptor integrins. This recognized region of RGD may be referred to as polypeptides ("peptides) containing the RGD sequence, and such RGD peptides are known inhibitors of integrin function.

Integrin inhibitors containing an RGD sequence are described, for example, in EP 0 770 622 A2. The described compounds inhibit in particular the interactions of β3 and / or β5 integrin receptors with ligands and are particularly active in the case of integrins a _v e ₃ , a _v e ₅ and α _Ν β ₃ , but also at receptors a _v Pi, a _v e ₆ and a _v e ₈ . This effect can be demonstrated, for example, as described by JW Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). Moreover, these compounds exhibit anti-inflammatory effects.

Many antagonists lacking the RGD sequence have been developed from integrin inhibitors containing the RGD sequence. Such integrin inhibitors without RGD sequences have been shown, for example, in patents

WO 96/00730 A1, WO 96/18602 A1, WO 97/37655 A1, WO 97/06791 A1, WO 97/45137 A1,

WO 97/23451 A1, WO 97/23480 A1, WO 97/44333 A1, WO 98/00395 A1, WO 98/14192 A1,

WO 98/30542 A1, WO 99/11626 A1, WO 99/15178 A1, WO 99/15508 A1, WO 99/26945 A1,

WO 99/44994 A1, WO 99/45927 A1, WO 99/50249 A2, WO 00/03973 A1, WO 00/09143 A1,

WO 00/09503 A1, WO 00/33838 A1.

DE 1970540 A1 describes bicyclic aromatic amino acids having the effect of inhibitors of integrin a _v receptors, especially integrin a _v e ₃ and a _v e ₅ . These compounds are particularly active as adhesion receptor antagonists to the vitronectin a _v e ₃ receptor. This effect can be demonstrated, for example, as described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

WO 00/26212 A1 describes chromanon and chromanon derivatives with integrin inhibitors acting on integrin receptors a _v , in particular integrins a _v e ₃ and a _v e ₅ . These compounds are also particularly active as adhesion receptor antagonists to the vitronectin α _v e ₃ receptor.

Integrin inhibitors are considered to be preferred as pharmaceutically active substances in human and veterinary medicine, especially for the prevention and treatment of various disorders. In particular, their specific use is recommended for the treatment and prevention of circulatory diseases, thrombosis, infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, neoplastic diseases, osteolytic diseases, especially osteoporosis, angiogenesis and disorders resulting from angiogenesis, e.g. diabetic retinopathy, degeneration of the eye. macular, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubella glaucoma as well as ulcerative enteritis, Crohn's disease, multiple sclerosis, psoriasis and post-angioplasty restenosis.

PL 207 175 B1

Eye disease resulting from angiogenesis is the leading cause of blindness in America. While for the population over 65, vision loss is mainly due to age-related macular degeneration (AMD), for the population under 65, it is mainly due to retinopathy. diabetic.

The Wall Street Journal, March 6, 2000 gave an overview of the prevalence and current therapies of AMD. According to the article, AMD currently affects approximately 12 million Americans. AMD progressively destroys the macula that is responsible for central vision and color vision. In some cases, deterioration of central vision to a blurry spot may occur rapidly over weeks or months. There are two forms of the disease called "atrophic" and "exudative". Although exudative AMD affects only 10% of the total AMD-suffering population, it accounts for 90% of all AMD-related visual impairment.

Until recently, the only treatment for wet AMD was to direct a powerful laser beam onto damaged blood vessels to warm and coagulate them. However, only about 15% of patients suffering from wet AMD have been able to undergo this laser treatment. Other treatments are currently in the experimental phase. In an approach called photodynamic therapy, a low-power laser is combined with the injection of a light-absorbing dye. Another therapy is a more surgical approach and is called "restricted retinal translocation. In this therapy, leaky vessels are destroyed with a high-power laser, after separation and rotation of the retina from the outer wall of the eye.

US Patent 5,766,591 describes the use of _{RGD containing α ν} β ₃ antagonists for the treatment of patients who have neovascularization in retinal tissue. More specific use of these antagonists is recommended for the treatment of patients suffering from diabetic retinopathy, macular degeneration and neovascular glaucoma. However, no examples of this use are presented. Regarding the routes of administration, only general information is provided. In particular, intravenous, intraperitoneal, intramuscular, intracavitary and transdermal administration are mentioned. In all cases, the a _v e ₃ antagonists show a favorable selectivity for a _v e ₃ , stronger than for other integrins such as a _v e ₅ .

WO 97/06791 A1 describes the possibility of using a _v e ₅ antagonists to inhibit angiogenesis. As recommended for the a _v e ₃ antagonists in US Patent 5,766,591, the a _v e ₅ antagonists are recommended for the treatment of patients with diabetic retinopathy, macular degeneration and neovascular glaucoma. With regard to the routes of administration, the following administration methods are specifically mentioned: intravenous, intraocular, capsular, intramuscular, transdermal and oral.

It turned out that inhibitors of integrin receptors a _v e ₃ and / or a _v e ₅ have, with good tolerance, specific pharmacological and physicochemical properties, in particular, they can be used for the prevention and treatment of eye diseases resulting from ocular angiogenesis, after the inhibitor is injected into the eye. the vitreous body of the eye.

It also turned out that inhibitors of a _v e ₃ and / or a _v e ₅ integrin receptors, which are not polypeptides and do not contain RGD sequences, can also be used for the prevention and treatment of eye diseases resulting from ocular angiogenesis by injecting the inhibitor into the body the vitreous eye.

The invention relates to the use of an a _v e ₃ and / or a _v e ₅ inhibitor of formula II, in which

R ¹ is H or alkyl having 1-6 carbon atoms,

R ² is R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ ,

R ³ is H,

R ⁴ is H or = O,

R ⁵ is R ⁶ ,

R ⁷ , R ⁸ are independently absent from each other or are H,

R ⁷ , R ⁸ together also mean a bond,

X is -NH-, O or -CH2-,

Y is NH or O,

W, Z are independently absent or represent C (= O), NH, CONH or NHCO,

R ⁶ is 1H-imidazole-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 -yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl,

R ¹⁰ is H, alkyl of 1-6 carbon atoms, camphor-10-yl or benzyl,

R ¹¹ is H,

PL 207 175 B1

A is unsubstituted alkyl having 1-6 carbon atoms and m, n are independently 0, 1 or 2;

or a physiologically tolerable salt thereof for the preparation of a pharmaceutical composition for the prevention and / or treatment of ocular diseases resulting from ocular angiogenesis, the composition comprising a therapeutically effective amount of an α _ν β ₃ inhibitor and / or α _ν β ₅ inhibitor sufficient to inhibit ocular angiogenesis, and It is administered by injection into the vitreous body of the eye.

The vitreous body is located at the back of the eye and occupies about four-fifths of the eyeball cavity behind the lens. The vitreous body is made up of a gelatinous material called "vitreous humor". The vitreous fluid of the normal human eye is composed of approximately 99% water and 1% macromolecules containing collagen, hyaluronic acid, soluble glycoproteins, sugars and other low molecular weight metabolites.

For intravitreal drug administration, an a _v e ₃ and / or a _v e ₅ inhibitor sufficient to inhibit ocular angiogenesis may be injected directly into the vitreous by passing the needle through a flat surface (pars foam).

A therapeutically effective amount is an amount of the inhibitor sufficient to produce a measurable inhibition of angiogenesis in eye tissue when injected into the vitreous. Typically, the amount of a _v e ₃ and / or a _v e ₅ inhibitor is from about 0.5 µg to about 5 mg.

The use according to the invention is particularly useful for the prevention and / or treatment of diabetic retinopathy, macular degeneration, myopia and histoplasmosis.

Preferred inhibitors of the invention are the a _v e ₃ and / or a _v e ₅ inhibitors which can be represented by the specific formula Ile corresponding to formula II, but wherein in Ile R ¹ is H or an alkyl having 1-6 carbon atoms,

R ² is R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ ,

R ³ is H,

R ⁴ is H or = O,

R ⁵ is R ⁶ ,

W, Z are independently absent or represent C (= O), NH, CONH or NHCO,

X is -NH-, O or -CH2-,

Y is NH or O,

R ⁶ is 1H-imidazole-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 -yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl,

R ¹⁰ is H, alkyl of 1-6 carbon atoms, camphor-10-yl or benzyl,

R ¹¹ is H,

A is unsubstituted alkyl having 1-6 carbon atoms and m, n are each independently 0, 1 or 2.

The compounds of formula II and the detailed formula Ile are described in DE 197 05 450 A1. Correspondingly, the substituents of formula II and the detailed formula Ile, respectively, have the same meanings as defined for the substituents of formula I and the corresponding formula I on page 2, lines 3 to 43, and on page 5, line 58 to page 7, line 30 respectively of the description Patent DE 197 05 450 A1. The definition of the substituents is given on page 4 line 35 to page 5 line 56 of DE 197 05 450 A1.

_{The following inhibitors a v} e ₃ and / or a _v e ₅ are particularly preferred for use according to the invention: (2S) -2- (2,2-dimethylpropyloxycarboxamido) -3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylethyl] - (2S) -2H-1,4-benzoxazine-3-one-6-yl} propionic;

(2S) -3- {2- [3- (1H-Imidazol-2-ylamino) propyl] -chroman-6-yl} -2- (2,2-dimethylpropoxycarboxamido) propionic acid;

(2S) -3- {2- [3- (1H-Imidazol-2-ylamino) propyl] -chroman-6-yl} -2- (butylsulfonamido) -propionic acid;

(2S) -2 - [(R) -camhorsulfonamido] -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazine-3-one- 6-yl) propionic;

and their physiologically tolerable salts.

The particular suitability of the compounds described above for use in the treatment of ocular diseases has been confirmed experimentally with representative compounds.

Inhibition of angiogenesis following intravitreal administration of compounds can be demonstrated by quantifying neovascularization in the eye after stimulating angiogenesis and subsequent intracorporeal administration

PL 207 175 B1 vitreous inhibitor α _ν β ₃ and / or α _ν β ₅ . A suitable model to demonstrate the inhibitory effect of an a _v e ₃ and / or a _v e ₅ inhibitor on angiogenesis is, for example, the rabbit corneal micro-pocket model described by Shaffer RW et al., In Molecular, Cellular, and Clinical Aspects of Angiogenesis, Maragoudakis E. (ed.). Plenum Press, New York, 241ff. (1996). In this model, angiogenesis is stimulated by implanting a Hydron tablet containing angiogenesis inducing cytokines, for example, fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) into the cornea. After implantation, the active compound is tested by paralimbic intravitreal injection. Effects on neovascularization are measured at fixed intervals by visual inspection with a microscope, photographing, and computerized rating using photographic quantification.

As an alternative to administration of an angiogenesis inducing cytokine, induction of angiogenesis can also be accomplished by laser photocoagulation as described, for example, by Murata T. et al., IOVS, 41, 2309ff. (2000).

The invention provides compositions suitable for the prevention and treatment of eye diseases caused by angiogenesis, comprising a therapeutically effective amount of the inhibitor and _v e ₃ and / or ₅ and _v e sufficient to inhibit angiogenesis of the eye and injected into the vitreous body of the eye of the patient.

The composition used for administering the compound to the vitreous body of the eye may be in any form suitable for intravitreal administration by injection through a small diameter cannula suitable for intravitreal injection. Examples of injection forms are solutions, suspensions or colloidal suspensions.

Compositions used for injection into the vitreous body contain physiologically compatible carriers together with an appropriate agent as described and the active ingredient dissolved or suspended therein. The term "pharmaceutically acceptable according to the invention" means compositions, carriers, diluents and reagents which define materials which can be administered into the vitreous body of a mammal without causing undesirable physiological effects. The preparation of injectable pharmacological compositions which contain dissolved or suspended active substances is well known in the art and requires no composition limitation. Manufacturing can also mean emulsifying. The active ingredient may be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient in amounts suitable for the therapeutic uses of the invention. Suitable excipients are, for example, water, saline, sorbitol, glycerol or the like, and combinations thereof. In addition, if appropriate, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like which aid the effectiveness of the active ingredients. The composition may also contain viscosity enhancing agents such as hyaluronic acid. The pharmaceutical composition of the invention may contain pharmaceutically acceptable salts of the ingredients. The pharmaceutically acceptable salts include acid addition salts which are formed from inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, tartaric, mandelic and the like. The salts formed from free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. HCl is a particularly preferred salt.

Physiologically tolerable carriers are known in the art. Examples of liquid carriers are sterile aqueous solutions, containing no materials other than the active substances and water, or containing buffers such as sodium phosphate at physiological pH, physiological saline or both, such as saline-buffered phosphate. In addition, aqueous vehicles may contain more than one buffer salt, and salts such as sodium and potassium chloride, sorbitol, and other solutions.

Depending on the form of administration, the active compound can be released immediately or over a long period of time. Sustained release compositions are advantageous because injection frequency can then be reduced.

One way to achieve sustained release kinetics is to dip or encapsulate the active compound into the nanoparticle. The nanoparticles can be administered in the form of a powder, a mixture of a powder with added excipients or as suspensions. Colloidal suspensions of nanoparticles are preferred because they can be easily administered with a small diameter cannula.

Nanoparticles are particles with a diameter from about 5 nm to about 1000 nm. The term "nanoparticles according to the invention means molecules formed by means of a polymer matrix,

The material in which the active compound is dispersed are also known as "nanospheres", and also mean nanoparticles formed from a core containing the active compound that is surrounded by a polymer membrane, are also called "nanocapsules." For administration to the vitreous body of the eye, the nanoparticles preferably have a diameter of from about 50 nm to about 500 nm, especially from about 100 nm to about 200 nm.

Nanoparticles can be made in situ by polymerization of dispersed monomers or by means of preformed polymers. As in situ generated polymers are often non-biodegradable and / or contain toxic coproducts, nanoparticles formed from preformed polymers are more preferred. Preformed polymer nanoparticles can be produced by various techniques, i.e. emulsion evaporation, solvent displacement, salting-out and emulsifying diffusion.

Emulsion evaporation is a classic technique for obtaining nanoparticles from preformed polymers. In this technique, the polymer and the active compounds are dissolved in a water-immiscible organic solvent which is emulsified in an aqueous solution. The crude emulsion is then subjected to a high energy source such as an ultrasonic instrument or passed through high pressure homogenizers or microfluidizers to reduce particle size. The organic solvent is then removed by heating and / or by exposure to vacuum to give nanoparticles with a diameter of about 100 nm to about 300 nm. Usually, methylene chloride and chloroform are used as organic solvents because they are water-insoluble, have good solubilizing properties, are easily emulsifiable and are highly volatile. However, the use of such solvents can be dangerous due to their physiological tolerance. Moreover, the high shear forces necessary to reduce the particle size can damage the polymer and / or the active compound.

The solvent displacement process was first described in EP 0 274 961 A1. In this process, the active compound and the polymer are dissolved in an organic solvent which is miscible with all ratios of water. This solution is introduced with gentle agitation into the aqueous solution containing the stabilizer, as a result of which nanoparticles spontaneously form. Examples of suitable organic solvents and stabilizers are acetone or ethanol, and polyvinyl alcohol, respectively. Chlorinated solvents and shear stresses are preferably avoided. The mechanism of nanoparticle formation has been elucidated by interfacial turbulence induced during solvent displacement (Fessi H. et al., Int. J. Pharm. 55 (1989) R1-R4). More recently, a solvent displacement technique is disclosed in WO 97/03657 A1, in which an organic solvent containing an active compound and a polymer is introduced into an aqueous solution without agitation.

The salting-out technique was first described in WO 88/08011 A1. In this technique, a solution of the water-soluble polymer and active compound in a water-soluble organic solvent, preferably acetone, is mixed with a concentrated viscous aqueous solution or gel containing a colloidal stabilizer and a salting out agent. Sufficient water is added to the resulting oil-in-water emulsion to diffuse into the aqueous phase and to induce rapid diffusion of the organic solvent into the aqueous phase, leading to interfacial turbulence and formation of nanoparticles. The organic solvent and the salting-out agent remaining in the nanoparticle suspension are gradually eliminated by repeated washing with water. Alternatively, the solvent and the salting-out agent can be eliminated by crossflow filtration.

In the emulsifying-diffusing process, the polymer is dissolved in a water-saturated organic solvent that is partially water-soluble. This solution is mixed with an aqueous solution containing a stabilizer, whereby an oil-in-water emulsion is formed. Water is added to this emulsion, which causes the diffusion of the solvent to the outer phase, accompanied by the formation of nanoparticles. Each drop of the emulsion leads to several nanoparticles during the formation of the particles. As this phenomenon cannot be fully explained by the convection effect caused by interfacial turbulence, it has been proposed that diffusion of the organic solvent from the crude emulsion droplets carries the active compound molecules and the polymer phase into the aqueous phase, resulting in local supernaturations, of which the polymer aggregates as nanoparticles (Quintanar-Guerrero D. et al. Colloid. Polym. Sci. 275 (1997) 640 - 647). Preferably, pharmaceutically acceptable solvents such as propylene carbonate or ethyl acetate can be used as organic solvents.

In the process described above, nanoparticles can be formed with different types of polymers. For use according to the invention which comprises injecting the formula into the vitreous

In the eye, the nanoparticles are preferably made of biocompatible polymers. The term "biocompatible" means a material that, when introduced into a biological environment, does not have a significant effect on that biological environment. Among the biocompatible polymers, those that are biodegradable are preferred. The term "biodegradable" means material that, when introduced into a biological environment, is enzymatically or chemically degraded into smaller molecules that can then be eliminated.

Biodegradable polymers are well known in the art. Examples are polyesters of hydroxycarboxylic acids such as poly lactic acid (PLA), poly glycolic acid (PGA), polycaprolactone (PCL), lactic acid copolymers and glycolic acid (PLGA), copolymers of lactic acid and caprolactone, polypsilone caprolactone, polyhydroxy butyric acid and poly (ortho) esters, polyurethanes, polyanhydrides, polyacetals, polydihydropyrans, polycyanoacrylates, natural polymers such as alginates and other polysaccharides, including polysaccharides collagen and albumin.

Liposomes are another drug delivery system that is easy to inject. Accordingly, according to the invention, the active compounds can also be administered to the vitreous body of the eye in the form of a liposomal delivery system. Liposomes are well known in the art. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine, phosphatidylcholine. Liposomes that are useful in the practice of the invention include all types of liposomes including, but not limited to, small multilamellar vesicles, large multilamellar vesicles, and multilamellar vesicles.

EXAMPLE

The efficacy of intravitreal administration of an α _ν β ₃ and / or α _ν β ₅ inhibitor was tested in the rabbit corneal micro-pocket model as described by Shaffer RW (see above). An example of a _v e ₃ and / or a _v e ₅ inhibitor in the experiment was 2- (2,2-dimethylpropyloxycarboxamido) -3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylethyl] - 2H-1,4-benzoxazine-3-one-6-yl} propionic. Hydron tablets containing basic fibroblast growth factor (bFGF) were used to induce angiogenesis. The preparation of bFGF-containing implants was carried out by placing Hydron [poly (hydroxyethyl) methacrylate] in specially prepared Teflon pins with 2.5 mm core hollow in the surface. Approximately 12 µl of material was placed in each pin and polymerized overnight under a sterile cover, then sterilized by ultraviolet irradiation.

The experiment included 10 animals; which a tablet was implanted into each eye into a surgically prepared "pocket in the central stroma (stroma) of the rabbit cornea. The surgical procedure was performed using a sterile technique using a Moeller-Wedel Microflex operating microscope (Haag-Streit Company, Germany) equipped with a translucent mirror and a camera for photographic recording of the corneal image. An A 69 Beaver blade was used to make "3mm by 5mm pockets". The stroma was cut circumferentially with a spatula and the tablet was implanted with a margin at the periphery 2 mm from the perimeter (limbus). Immediately after implantation of the Hydron tablet containing bFGF, 5 out of 10 animals were administered by intravitreal injection of 100 μl of a drug solution containing 2.0 mg / ml of 2- (2,2-dimethylpropyloxycarboxamido) -3- {3,4-dihydro-2- [ N- (2-imidazolyl) carbamoylethyl] -2H-1,4-benzo-xazine-3-one-6-yl} propionic acid solubilized in physiological saline. For comparison, the same procedure was performed on 5 animals using only saline. The eye implantation was then photographed and the area of neovascularization was measured at fixed intervals. The results obtained 5 and 7 days after implantation are presented in the table. An overview of the results obtained 5, 7, 10, and 14 days after implantation is presented in Table 1.

PL 207 175 B1

T a b e l a 1:

single intravitreal injection (day 0), 100 μΙ, 20 mg / ml drug = 2 mg / eye

days after implantation 5 7 10 14 inhibition [%] 56.3 13.4 45.8 40.0 Reference Bow Reference Bow Reference Bow Reference Bow Average area [mm ² ] 3.91 1.71 5.37 4.65 9.41 5.10 16.56 9.94 S.D. 1.84 1.29 1.86 2.11 2.97 2.26 5.40 3.31 CV% 47.06 75.44 34.64 45.38 31.56 44.31 32.61 33.30 n 10 9 10 9 10 9 10 7

TABLE 1: Single intravitreal injection efficacy (day 0) of 2- (2,2-dimethylpropyloxycarboxamido) -3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylethyl] -2H- acid 1,4-benzoxazine-3-one-6-yl} propionic acid against bFGF-stimulated corneal angiogenesis, 5, 7, 10 and 14 days after implantation.

The results obtained clearly demonstrate the beneficial effect of the compound of the invention. Although only one dose of the α _ν β ₃ and / or α _ν β ₅ inhibitor is shown and the drug formulation was a solution, strong inhibition of neovascularization was achieved for many days.

Claims (7)

Patent claims 1. Use of an α _ν β ₃ and / or α _ν β ₅ inhibitor of formula II, wherein R ¹ is H or alkyl having 1-6 carbon atoms, R ² is R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ , ₃ R ³ is H, R ⁴ is H or = O, R ⁵ is R ⁶ , R ⁷ , R ⁸ are independently absent from each other or are H, R ⁷ , R ⁸ together also mean a bond, X is -NH-, O or -CH2-, Y is NH or O, W, Z are independently absent or represent C (= O), NH, CONH or NHCO, R ⁶ is 1H-imidazole-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5 -yl, 1-A-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl, R ¹⁰ is H, alkyl of 1-6 carbon atoms, camphor-10-yl or benzyl, R ¹¹ is H, A is unsubstituted alkyl having 1-6 carbon atoms and m, n are independently 0, 1 or 2; or a physiologically tolerable salt thereof for the preparation of a pharmaceutical composition for the prevention and / or treatment of ocular diseases resulting from ocular angiogenesis, the composition comprising a therapeutically effective amount of an α _ν β ₃ inhibitor and / or α _ν β ₅ inhibitor sufficient to inhibit ocular angiogenesis, and It is administered by injection into the vitreous body of the eye. 2. The use according to claim 1 The method of claim 1, characterized in that the inhibitor of α _ν β ₃ and / or α _ν β ₅ is: (2S) -2- (2,2-dimethylpropyloxycarboxamido) -3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylethyl] - (2S) -2H-1,4-benzoxazine-3 -one-6-yl} propionic; (2S) -3- {2- [3- (1H-Imidazol-2-ylamino) propyl] -chroman-6-yl} -2- (2,2-dimethylpropoxycarboxamido) propionic acid; (2S) -3- {2- [3- (1H-Imidazol-2-ylamino) propyl] -chroman-6-yl} -2- (butylsulfonamido) -propionic acid; or (2S) -2 - [(R) -camhorsulfonamido] -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazine-3-one -6-yl) propionic; PL 207 175 B1 3. Use according to claim 1 The compound of claim 1 wherein the therapeutically effective amount of the compound is from about 0.5 Pg to 5 mg. 4. Use according to claim 1 The method of claim 1 wherein the eye disease is diabetic retinopathy. 5. Use according to claim 1 5. The method of claim 1 wherein the eye disease is macular degeneration. 6. Use according to claim 1 The method of claim 1 wherein the eye disease is myopia. Use according to claim 1 6. The method of claim 1, wherein the ophthalmic disease is ocular histoplasmosis.